Frontline mRCC Paradigm Crowds Among Immune-Based Treatment Options

The emergence of multiple combination regimens with immunotherapy and tyrosine kinase inhibitors (TKIs) has been welcome for the frontline treatment of patients with metastatic renal cell carcinoma (mRCC); however, without head-to-head comparative data, treatment selection has become individualized based on available patient characteristics. Those patients deemed eligible for immunotherapy are then further stratified to either standard of care combination regimens or to single-agent immunotherapy, an increasingly less common approach, said Primo Lara, Jr, MD, in a virtual presentation during the 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, a program hosted by Physicians’ Education Resource®, LLC (PER®).¹

“When you’re elbow-to-elbow with an individual with mRCC, you must stratify risk, seek multidisciplinary input, and always consider active surveillance and cytoreduction for the appropriate patient,” said Lara, director of the University of California (UC) Davis Comprehensive Cancer Center, professor of medicine, and executive associate dean for Cancer Programs at UC Davis School of Medicine.

“[Next], address that patient’s eligibility for immunotherapy. Immune-based combination therapies [are] the standard of care in 2021, but there will be some subset of patients who you consider for monotherapy, whether with an immunotherapy agent or a VEGFR[-directed] TKI. As time goes on these subsets [of patients] will keep diminishing as we improve the performance of our combination therapies,” Lara added.

Candidate Determination for mRCC Treatment Strategies

Risk stratification should be considered prior to making any treatment-related decisions as some patients may be eligible for active surveillance, said Lara. Additionally, risk score, per the International Metastatic RCC Database Consortium can inform eligibility for cytoreductive nephrectomy.

“The decision [of whether to pursue cytoreductive nephrectomy] must be individualized to the patient according to risk of recurrence, regression, and death,” said Lara. “Most favorable-risk patients and some intermediate-risk patients remain candidates for cytoreduction, especially those who have large and/or symptomatic tumors with low-volume metastatic disease.”

Highly selected patients may also be candidates for metastasectomy. Although data are mostly limited to retrospective studies, patients with good performance status who have isolated or oligometastatic disease, a disease-free interval of longer than 2 years post nephrectomy, no lymph node involvement, and/or lung-only disease may benefit from metastasectomy, Lara explained.

Combination Immunotherapy Strategies Win Out Over Single Agents

Lara explained that it is important to recognize which patients are not eligible for immune-based therapies, including those with active autoimmune disease who are likely to develop unacceptable toxicity from immunotherapy. Other patients who should not receive immunotherapy are those with a history of solid organ transplantation, those receiving supraphysiologic corticosteroids or chronic immunosuppressive therapy, and those whose have a personal preference against intravenous treatment administration.

If a patient is indicated as a candidate for immunotherapy, nuanced treatment selection is needed to determine whether a single-agent or combination regimen is optimal, Lara said.

“Monotherapy has its advantages. It is lower cost, simpler, and better tolerated than combination therapy. [It also] offers a reduced risk of drug-drug interactions, and, by the mere fact that there is only 1 drug being given, adherence is likely to be higher,” said Lara.

Historically, the frontline mRCC paradigm was dominated by single-agent angiogenesis inhibitors, such as sunitinib (Sutent), pazopanib (Votrient), cabozantinib (Cabometyx), axitinib (Inlyta), sorafenib (Nexavar), and bevacizumab (Avastin). However, the field expanded rapidly in recent years favoring combination regimens as standard, frontline options.

Across all risk groups, combinations of immunotherapy and TKIs including, pembrolizumab (Keytruda)/axitinib, nivolumab (Opdivo)/cabozantinib, pembrolizumab/lenvatinib (Lenvima), and avelumab (Bavencio)/axitinib, have demonstrated activity in patients with RCC compared with sunitinib alone.

The combination of cabozantinib and nivolumab, which was approved by the FDA for the frontline treatment of patients with advanced RCC on January 22, 2021, demonstrated a 49% reduction in the risk of disease progression or death compared with sunitinib.²

Data from CheckMate 9ER (NCT03141177 ) demonstrated that the combination elicited a median progression-free survival (PFS) of 16.6 months (95% CI, 12.5-24.9) vs 8.3 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.51; 95% CI, 0.41-0.64; P < .0001). At a median follow-up of 10.6 months, the median overall survival (OS) was not reached (NR) in either arm but demonstrated a 40% reduction in the risk of death with the combination (HR, 0.60; 95% CI, 0.40-0.89; P = .0010).

Most recently, findings from the phase 3 CLEAR trial (NCT02811861), presented during the 2021 Genitourinary Cancers Symposium, demonstrated an improvement in OS, PFS, and overall response rate (ORR) with the combination of frontline lenvatinib and pembrolizumab vs sunitinib in patients with advanced RCC.³

Although the combination is not approved for patients with RCC, results showed that the median PFS was 23.9 months (95% CI, 20.8-27.7) with the combination compared with 9.2 months (95% CI, 6.0-11.0) with sunitinib. The median OS was NR in either arm but represented a 34% reduction in the risk of death with the combination vs sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

The CLEAR trial also demonstrated improved PFS and ORR, but not OS, with the combination of lenvatinib plus everolimus (Afinitor) vs sunitinib.

“This trial was designed to compare each of the doublets to the sunitinib control arm, but the doublets were not designed to be compared with each other,” added Lara.

Another approved option for patients is the immunotherapy doublet of nivolumab plus ipilimumab (Yervoy) is an approved frontline option for patients with intermediate- or poor-risk disease.⁴

Other Nuanced Options to Consider in Specific Patients With mRCC

Frontline checkpoint inhibitor monotherapy with either pembrolizumab or nivolumab may be considered in select patients who are ineligible for or refuse VEGFR-directed TKI–containing combinations or are averse to ipilimumab. Single-agent pembrolizumab has demonstrated an ORR of 33.6% (95% CI, 24.8%-43.4%) and a median PFS of 6.9 months (95% CI, 5.1-NR) in patients (n = 110) with mRCC.⁵ Nivolumab monotherapy demonstrated an ORR of 31.7% (95% CI, 27.4%-46.1%) and a median PFS of 8.3 months (95% CI, 5.5-10.9) in patients with mRCC (n = 123).⁶

Alternatively, VEGFR-directed TKI monotherapy with cabozantinib may be considered for certain patients who are ineligible for, intolerant of, or refuse immunotherapy. Patients with bone-only metastases or non–clear cell histology, such as papillary RCC, may also be considered.

Data from the open-label phase 2 PAPMET SWOG S1500 trial (NCT02761057) was presented during the 2021 Genitourinary Cancers Symposium. The trial randomized patients with metastatic papillary RCC who had 0 or 1 prior line of therapy that was not sunitinib to receive single-agent sunitinib, cabozantinib, crizotinib (Xalkori), or savolitinib. The median PFS was 9.0 months with cabozantinib, 2.8 months with crizotinib, 3.0 months with savolitinib, and 5.6 months with sunitinib, showing that cabozantinib monotherapy was superior to sunitinib in this patient population (HR, 0.60; 95% CI, 0.37-0.97; P = .019).⁷

Additionally, responses favored cabozantinib vs sunitinib irrespective of papillary RCC subtype (type 1, type 2, mixed/other, or missing/not available).

Other treatment considerations for frontline therapy include high-dose interleukin-2 (IL-2) monotherapy and mTOR inhibitor monotherapy; however, these options are reserved for a very limited number of patients. High-dose IL-2 may be used in robust patients with excellent performance status and normal end-organ function, but it requires inpatient treatment and is associated with significant toxicity. mTOR inhibitors, such as temsirolimus (Torisel), have lost their place in the landscape for the treatment of patients with poor-risk mRCC.

“Temsirolimus was originally tested in a registration trial in a poor-risk context using composite criteria, but in the era of more active, life-prolonging therapies there is very little justification for routine temsirolimus use,” Lara said.

Taken collectively, treatment selection for patients with mRCC requires careful consideration of data from multiple frontline regimens. “Cost, convenience, physician experience, and patient preference will have to always apply [to treatment selection. Being an astute clinician requires you to incorporate all of these considerations at the bedside,” Lara concluded.

References

1. Lara P. Targeted therapies in renal cell carcinoma: monotherapy vs combination therapy. Presented at: 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies. March 12-13, 2021; virtual.
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257.
3. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. New Engl J Med. Published online ahead of print February 13, 2021. doi:10.1056/NEJMoa2035716
4. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell
5. Tykodi SS, Donskov F, Lee JL, et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. J Clin Oncol. 2019;37(suppl 15):4570. doi:10.1200/JCO.2019.37.15_suppl.4570
6. Atkins MB, Jegede O, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). J Clin Oncol. 2020;38(suppl 15):5006. doi:10.1200/JCO.2020.38.15_suppl.5006
7. Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet.2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5